We request an administrative supplement under this notice to support our ongoing studies to expand our understanding within the scope of the questions asked in the parent grant. Trisomy 21 that characterizes Down syndrome (DS) is a common congenital condition affecting greater than five millions people worldwide. In addition to many developmental abnormalities associated with DS, there is an increasing awareness that adolescents and adults with DS also have a much higher incidence of obesity, insulin resistance, and diabetes. The underlying basis for this metabolic dysregulation is largely unknown. A majority of DS-related studies are focused on cognitive deficits. Beyond the clinical observations, few, if any, studies have been conducted to determine the physiological underpinnings of metabolic impairments seen in DS patients. Thus, the research supplement will allow us to fill a major knowledge gap?a largely overlooked area?of DS research. We seek to test the hypothesis that increased expression of large number of transcribed sequences in every cell types found in trisomy 21 disrupts homeostatic mechanisms in liver, muscle, pancreas, and adipose tissue to maintain normal glucose and lipid metabolism. We will leverage a novel and more representative mouse model of DS, in which the MAC21 mice contain a near complete copy of human chromosome 21. The proposed research supplement fits well with the overarching goals of our parent RO1 grant (DK084171) to understand mechanistic basis of impaired sugar and fat metabolism in the context of obesity and type 2 diabetes.